The proposed project is centered on cancer susceptibility gene discovery. This project is based on the hypothesis that a subset of individuals with multiple primary cancers has an underlying susceptibility gene mutation that is common to all tumors in that individual. Earlier studies using population-based tumor registries have demonstrated an increased risk of melanoma as a second malignancy in women diagnosed with breast cancer. Conversely, an increased risk of breast cancer has been demonstrated in women who have been previously diagnosed with melanoma. This bi-directional increased risk of a second malignancy deserves further attention and is suggestive of a common mechanism as the etiology of these two tumors. To this end, we intend to define and characterize a population of women who have been diagnosed with both breast cancer and melanoma. Outside of defined syndromes, little had been documented regarding multiple primary cancers. What data exist strongly support the hypothesis that women with multiple primary cancers are more likely to harbor germline susceptibility alleles than those with a single malignancy. We hypothesize that women with the multiple primary cancers, breast and melanoma, represent a clinically significant variation in disease phenotype for one of the known candidate genes. We will screen this population for germline and somatic mutations in genes known to be involved in cancer predisposition or progression. In addition, we will use array-based comparative genomic hybridization (aCGH) to identify the critical genetic changes that are necessary to transform normal melanocytes or breast epithelium into cells with malignant potential. A DNA-based microarray platform using bacterial artificial chromosomes (BACs) containing human genomic DNA representative of the entire genome at 1-2 Mb intervals, will be utilized to define regions of chromosomal gain and loss using DNA from breast and melanoma tumors both from a single individual as well as versus matched sporadic tumors. The overall objective of this proposal is the identification of additional cancer susceptibility genes, which will enable the study of the genes themselves and advance our understanding of the etiology of breast cancer and malignant melanoma.